AACR highlights: promise for treating pancreatic cancer.

P ancreatic cancer, one of the deadliest cancers, may lead to new treatments based on biotypes that are common to many cancers, according to Andrew Biankin, MBBS, Ph.D. , head of pancreatic research at the Garvan Institute of Medical Research in Sydney. “In the current system, the assumption is that cancers are more related to the organ of origin,” Biankin said, adding that using cancer biotypes to target shared genetic mutations across cancers could change treatment for this diffi cult malignancy. Pancreatic cancer is the fourth-leading cause of cancer death in the United States, and the average 5-year survival rate is less than 4%. Biankin, part of a panel session called Advances in Pancreatic Cancer at the American Association for Cancer Research (AACR) annual meeting in Orlando, April 2 – 6, proposed a pilot study, using sequencing data from the International Genome Consortium, to address the level of evidence required to validate assays in the multimutation approach. His research team is now sequencing 400 tumors taken from patients with advanced disease. “It’s a work in progress and a publicly funded effort,“ said Anirban Maitra, MBBS., professor of pathology and oncology at John Hopkins ’ Sol Goldman Pancreatic Cancer Research Center and one of the session’s cochairmen. “The pilot trial would be proof of principle that biotyping can work.” Instead of taking a one-size-fi ts-all approach to cancer, Maitra said, researchers would match shared mutations to a particular drug. For example, a genetic error such as Her2 amplifi cation, found in certain breast cancers and in 2% – 3% of pancreatic cancers, might allow some pancreatic patients to be candidates for anti-Her2 drugs, such as trastuzumab or lapatinib. “But, for targeted therapy to work, the target must be present in that cancer cell, even if the percentage of cancers harboring that change is small,” Maitra stressed. “What’s important is that patient selection be done appropriately.” Otherwise, treatments will fail, or benefi ts will be incremental, he said, as seen in recent studies combining the targeted therapy erlotinib with gemcitabine. Pancreatic cancer is genetically complex. Scientists have identifi ed four mutated genes so far, which occur in at least half of these cancers, along with many less-frequent mutations. The most prevalent mutation is in the K-ras gene. More than 90% of pancreatic cancers carry this mutation, making it a desirable target for new treatments. So far, researchers have tried using farnesyltransferase inhibitors to suppress the gene, with mixed success. Some experts also believe the gene holds promise for detecting early disease someday, a long-elusive goal because most patients are diagnosed at late stage. Other highlights from the session include the following: Early results from a study of abraxane (nab-paclitaxel) with gemcitabine have shown encouraging clinical benefi t in pancreatic cancers, suggesting that the combination could become the new standard of patient care, said Jordan Berlin, M.D., clinical director of the gastrointestinal oncology program at Vanderbilt Ingram Cancer Center in Nashville, Tenn. In phase III studies, investigators are using nanoparticles to pierce holes in the stroma’s protective fi brous wall, a tactic offering more effi cient drug delivery than paclitaxel alone. The next step, now in phase I and I/II studies, involves targeting the hedgehog signaling pathway, using the hedgehog inhibitor GDC-0449 with and without gemcitabine. Because the pancreas has such an active stroma and primary pancreatic tumors consist mostly of compromised stromal tissue, Berlin said, this approach is promising. “But we need to learn more about [the stroma].” • One new drug candidate targets the ATDC gene, which aids pancreatic cancer cell survival by heightening resistance to DNA-damaging drugs and increasing cell proliferation, said Diane Simeone, M.D., director of the Pancreatic Tumor Program at the University of Michigan Comprehensive Cancer Center. “The gene is overexpressed in almost 90% of pancreatic cancers,” she told the audience at AACR. “The question is, does it cooperate with K-ras to promote disease?” For mice, the answer is yes. Targeted nanovectors silenced ATDC in established tumors in mice, inhibiting tumor growth and rendering the tumors more sensitive to chemotherapy and radiation, she said. That finding raises the hope that the Andrew Biankin, MBBS, Ph.D. “In the current system, the assumption is that cancers are more related to the organ of origin.”